Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.
Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.
Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid.
According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.
According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.
PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.
7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.
We have discovered a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
7-Chloro -1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro -1H-1-benzazepine is a key intermediate for the preparation of tolvaptan.
We have also discovered an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The process of the invention results in higher yields compared with the known process of using organic base in the reaction.
7-Chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is a key intermediate for the preparation of tolvaptan.
We have also discovered an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The process of the invention results in higher yields compared with the known process of using organic base in the reaction.
Thus, an object of the present invention is to provide a novel process for the preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
Another object of the present invention is to provide an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
Yet another object of the present invention is to provide an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.